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Review series

Myocardial ischemia-reperfusion injury:

a neglected therapeutic target
Derek J. Hausenloy and Derek M. Yellon
The Hatter Cardiovascular Institute, University College London, London, United Kingdom.

Acute myocardial infarction (MI) is a major cause of death and disability worldwide. In patients with MI, the
treatment of choice for reducing acute myocardial ischemic injury and limiting MI size is timely and effective
myocardial reperfusion using either thombolytic therapy or primary percutaneous coronary intervention (PPCI).
However, the process of reperfusion can itself induce cardiomyocyte death, known as myocardial reperfusion
injury, for which there is still no effective therapy. A number of new therapeutic strategies currently under investigation for preventing myocardial reperfusion injury have the potential to improve clinical outcomes in patients
with acute MI treated with PPCI.
Introduction
Coronary heart disease (CHD) is the leading cause of death and
disability worldwide. According to the WHO, 7,254,000 deaths
worldwide (12.8% of all deaths) resulted from CHD in 2008. The
effects of CHD are usually attributable to the detrimental effects
of acute myocardial ischemia-reperfusion injury (IRI). IRI typically arises in patients presenting with an acute ST-segment elevation myocardial infarction (STEMI), in whom the most effective
therapeutic intervention for reducing acute myocardial ischemic
injury and limiting the size of myocardial infarction (MI) is timely
and effective myocardial reperfusion using either thrombolytic
therapy or primary percutaneous coronary intervention (PPCI).
However, the process of myocardial reperfusion can itself induce
further cardiomyocyte death, a phenomenon known as myocardial reperfusion injury (13). Although the process of myocardial
reperfusion continues to improve with more timely and effective
reperfusion and with advances in PCI technology and antiplatelet and antithrombotic agents for maintaining the patency of the
infarct-related coronary artery, there is still no effective therapy for
preventing myocardial reperfusion injury. In this respect, myocardial reperfusion injury remains a neglected therapeutic target for
cardioprotection in PPCI patients. In this article, the pathophysiology of myocardial lRI and the emerging therapeutic strategies
for protecting the heart from its detrimental effects are reviewed.
Pathophysiology of myocardial ischemic injury
Acute occlusion of the coronary artery in the STEMI patient subjects the myocardium supplied by that vessel to acute myocardial
ischemia, thereby demarcating the area at risk (AAR) of potential
MI, should the acute coronary occlusion be sustained or permanent. If the period of acute myocardial ischemia is prolonged
(more than 20 minutes) a wave front of cardiomyocyte death
begins in the subendocardium and extends transmurally over time
toward the epicardium (4).
The deprivation of oxygen and nutrient supply results in a
series of abrupt biochemical and metabolic changes within the
myocardium (Figure 1). The absence of oxygen halts oxidative
phosphorylation, leading to mitochondrial membrane depolarization, ATP depletion, and inhibition of myocardial contractile
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this article: J Clin Invest. 2013;123(1):92100. doi:10.1172/JCI62874.
92

function. This process is exacerbated by the breakdown of any

available ATP, as the F1F0 ATPase functions in reverse to maintain
the mitochondrial membrane potential, resulting in ATP hydrolysis and an increase in mitochondrial inorganic phosphate. In
the absence of oxygen, cellular metabolism switches to anaerobic
glycolysis, resulting in the accumulation of lactate, which reduces
intracellular pH (to <7.0). The intracellular accumulation of protons activates the Na+-H+ ion exchanger, which extrudes protons
from the cell in exchange for Na+ entry. The lack of ATP during
ischemia ceases function of the 3Na+-2K+ ATPase, thereby exacerbating the intracellular Na+ overload. In response, the reverse activation of the 2Na+-Ca2+ ion exchanger results in intracellular Ca2+
overloading as the cell tries to extrude Na+ (5).
Pathophysiology of myocardial reperfusion injury
After the onset of acute myocardial ischemia in patients with
STEMI, timely myocardial reperfusion using PPCI is essential to
salvage viable myocardium, limit MI size, preserve LV systolic function, and prevent the onset of heart failure. However, the reperfusion of acutely ischemic myocardium can independently induce
cardiomyocyte death (13), although this concept has been difficult to accept over the years. The four recognized forms of myocardial reperfusion injury are discussed in detail below, the first two
reversible and the second two irreversible.
Reperfusion-induced arrhythmias. The sudden reperfusion of acutely ischemic myocardium in STEMI patients undergoing PPCI may
be accompanied by ventricular arrhythmias, which usually selfterminate or are easily treated (6).
Myocardial stunning. The reversible post-ischemic contractile
dysfunction that occurs on reperfusing acute ischemic myocardium is referred to as myocardial stunning. This form of reperfusion injury results from the detrimental effects of oxidative
stress and intracellular calcium overload on the myocardial contractile apparatus (7).
Microvascular obstruction. Microvascular obstruction (MVO) was
first described by Krug et al. in 1966 as the inability to reperfuse
a previously ischemic region (8). The major contributing factors
include capillary damage with impaired vasodilatation, external
capillary compression by endothelial cell and cardiomyocyte
swelling, micro-embolization of friable material released from
the atherosclerotic plaque, platelet micro-thrombi, the release of
soluble vasomotor and thrombogenic substances, and neutrophil

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Figure 1
Schematic illustrating the main proponents of acute myocardial IRI. During acute myocardial ischemia, the absence of oxygen switches cell
metabolism to anaerobic respiration, resulting in the production of lactate and a drop in intracellular pH. This induces the Na+-H+ exchanger to
extrude H+ and results in intracellular Na+ overload, which activates the 2Na+-Ca2+ exchanger to function in reverse to extrude Na+ and leads to
intracellular Ca2+ overload. The Na+-K+ ATPase ceases to function in ischemia, exacerbating intracellular Na+ overload. The acidic conditions
during ischemia prevent the opening of the MPTP and cardiomyocyte hypercontracture at this time. During reperfusion, the electron transport
chain is reactivated, generating ROS. Other sources of ROS include xanthine oxidase (endothelial cells) and NADPH oxidase (neutrophils). ROS
mediate myocardial reperfusion injury by inducing the opening of the MPTP, acting as a neutrophil chemoattractant, and mediating dysfunction
of the sarcoplasmic reticulum (SR). This contributes to intracellular Ca2+ overload and damages the cell membrane by lipid peroxidation, inducing enzyme denaturation and causing direct oxidative damage to DNA. Reperfusion and reactivation of the Na+-H+ exchanger result in washout
of lactic acid, resulting in the rapid restoration of physiological pH, which releases the inhibitory effect on MPTP opening and cardiomyocyte
contracture. The restoration of the mitochondrial membrane potential drives calcium into the mitochondria, which can also induce MPTP opening.
Several hours after the onset of myocardial reperfusion, neutrophils accumulate in the infarcted myocardial tissue in response to the release of
the chemoattractants ROS, cytokines, and activated complement.

plugging (912). At coronary angiography in PPCI patients, MVO

manifests as sluggish coronary blood flow, impaired myocardial
blush grade, and a characteristic coronary flow velocity profile
(13). Importantly, 30%40% of PPCI patients in whom coronary
blood flow in the infarct-related coronary artery appears normal on coronary angiography have evidence of MVO as detected
by myocardial contrast echocardiography (14, 15), myocardial
perfusion nuclear scanning (16), or contrast-enhanced cardiac
MRI (17, 18). The presence of MVO is associated with a larger
MI size, a lower LV ejection fraction, adverse LV remodelling, and
worse clinical outcomes (15, 19, 20). In severe cases of MVO in
which there is significant damage to the endothelium, extravasation of blood into the interstitium can produce intramyocardial hemorrhage within the area of infarction, a feature that can
also be detected by cardiac MRI (21). No effective therapy currently exists for reducing MVO in patients who have undergone
PPCI. Whether MVO is actually an independent causative factor
of reperfusion-induced cardiomyocyte death or is merely a biomarker of severe myocardial IRI remains unclear.
Lethal myocardial reperfusion injury. Reperfusion-induced death
of cardiomyocytes that were viable at the end of the index isch

emic event is defined as lethal myocardial reperfusion injury (2).

The major contributory factors are discussed below and include
oxidative stress, calcium overload, mitochondrial permeability transition pore (MPTP) opening, and hypercontracture (3).
The existence of lethal myocardial reperfusion injury has been
inferred in both experimental MI models and in patients with
STEMI by the observation that therapeutic interventions applied
solely at the onset of myocardial reperfusion reduced MI size by
40%50% (3). This observation suggests that lethal myocardial
reperfusion injury may account for up to 50% of the final MI
size. Lethal myocardial reperfusion injury attenuates the full
benefits of myocardial reperfusion in terms of MI size reduction
and thus represents an important target for cardioprotection in
PPCI patients (see Figure 2). However, no effective therapy currently exists for reducing lethal myocardial reperfusion injury in
patients who have undergone PPCI.
Mediators of myocardial reperfusion injury
Experimental studies have identified several critical factors that
act in concert to mediate the detrimental effects of myocardial
reperfusion injury (see Figure 1).

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Figure 2
This figure illustrates the individual contributions of acute myocardial ischemic injury and myocardial reperfusion injury to final MI size
(expressed in arbitrary units) in STEMI patients up to 24 hours following PPCI. The black solid line depicts the individual contributions
to final MI size of acute myocardial ischemic injury and of myocardial
reperfusion injury. The green dashed line depicts the theoretical MI
size following PPCI based on acute myocardial ischemia alone in the
absence of myocardial reperfusion injury. The red dashed line depicts
the theoretical MI size based on acute myocardial ischemia alone in
the absence of PPCI. The presence of myocardial reperfusion injury
attenuates the benefit of PPCI in terms of the reduction of MI size.
Therefore, the administration of a therapeutic strategy as an adjunct to
PPCI that is capable of reducing myocardial reperfusion injury would
result in a smaller MI size (as depicted by the green dashed line) and
take advantage of full benefits of myocardial reperfusion. Figure modified from Cardiovascular Research (93).

Oxidative stress. In the first few minutes of myocardial reperfusion, a burst of oxidative stress (22, 23) is produced by a variety
of sources (Figure 1). This detrimental oxidative stress mediates
myocardial injury and cardiomyocyte death through a number
of different mechanisms (Figure 1). Based on these observations,
antioxidant therapy was naturally considered to be an appropriate
option to prevent such injury. However, both experimental and
clinical studies have reported mixed results with the administration of antioxidant therapy at the onset of myocardial reperfusion. The reason for this may in part be due the inability of the
antioxidant to enter the cell (24). In this regard, the discovery of
mitochondrial-specific antioxidants may be more effective (25).
Intracellular Ca2+ overload. Intracellular and mitochondrial Ca2+
overload begins during acute myocardial ischemia and is exacerbated at the time of myocardial reperfusion due to disruption of
the plasma membrane, oxidative stress-induced damage to the
sarcoplasmic reticulum, and mitochondrial re-energization (Figure 1). Mitochondrial re-energization allows the recovery of the
mitochondrial membrane potential that drives the entry of Ca2+
into mitochondria via the mitochondrial Ca2+ uniporter and subsequently induces the opening of the MPTP (Figure 1). Experimental studies have shown that pharmacologic antagonists of the sarcolemmal Ca2+ channel (26) or the mitochondrial Ca2+ uniporter
(27), administered at the onset of myocardial reperfusion, reduce
MI size by up to 50%. However, not all experimental studies using
this therapeutic strategy have been positive. Clinical studies of
calcium channel blockers administered at the onset of myocardial reperfusion have not shown beneficial results (28). The recent
94

identification of the mitochondrial Ca2+ uniporter (29) may result

in the discovery of a new class of specific inhibitors for targeting
lethal myocardial reperfusion injury.
The rapid restoration of physiological pH at the time of reperfusion.
During acute myocardial ischemia the intracellular pH decreases
to less than 7.0, whereas at reperfusion, physiological pH is rapidly restored by the washout of lactate and the activation of the
Na+-H+ exchanger as well as the Na+-HCO symporter. This pH
shift contributes to the cardiomyocyte death of lethal myocardial reperfusion injury (30) by permitting MPTP opening and
cardiomyocyte rigor hypercontracture in the first few minutes
of reperfusion. Reperfusion of ischemic animal hearts with an
acidic buffer can reduce MI size (31). Therefore, a potential treatment strategy for preventing lethal myocardial reperfusion injury
would be to slow the normalization of physiologic pH at the time
of myocardial reperfusion, which may be achieved via the pharmacologic inhibition of the Na+-H+ exchanger (5) or by slowing
the process of myocardial reperfusion, as in the case of ischemic
postconditioning (IPost) (32), which has been termed the pH
hypothesis by Cohen and Downey (33).
The MPTP: an important target for cardioprotection. Many of the
above proponents of myocardial reperfusion injury appear to
converge on the MPTP. The MPTP is a nonselective channel of
the inner mitochondrial membrane, the opening of which results
in mitochondrial membrane depolarization and uncoupling of
oxidative phosphorylation, leading to ATP depletion and cell
death (34, 35). In the setting of acute myocardial IRI, the MPTP
has been shown to remain closed during ischemia and only open
at reperfusion in response to mitochondrial Ca2+ and phosphate
overload, oxidative stress and relative ATP depletion, and rapid
pH correction (36). As such, preventing MPTP opening at the
time of reperfusion by administering known MPTP inhibitors
(such as the immunosuppressant cyclosporin A) at the onset of
myocardial reperfusion has been reported in experimental studies to reduce MI size by 40%50% in small and large animal MI
models (3740) and protect human atrial trabeculae subjected
to simulated IRI (41). As such, the MPTP provides an important
therapeutic target for preventing lethal myocardial reperfusion
injury (see section below).
Inflammation: guilty mediator or innocent bystander. It is unclear
whether the inflammatory response that accompanies an acute MI
contributes to the pathogenesis of lethal myocardial reperfusion
injury or whether it is a reaction to the acute myocardial injury (42).
Although experimental studies have reported significant reduction
of MI with therapeutic strategies designed to inhibit the inflammatory process at the time of myocardial reperfusion using antibodies against cell-adhesion molecules (4345) and the inhibition of
complement activation (46), corresponding clinical studies using
this therapeutic approach have been largely negative (4749).
Late myocardial reperfusion injury: extending the window of cardioprotection. The previously described stimulators of myocardial reperfusion injury all appear to operate in the first few minutes of myocardial reperfusion, providing a narrow window for reducing MI
size in PPCI patients. However, several other important processes
such as apoptosis and inflammation, which are also initiated during ischemia and continue over several hours into reperfusion, may
contribute to the development of lethal myocardial reperfusion
injury. These contributing pathways provide a potential second
therapeutic window for reducing MI size, even well after myocardial reperfusion has taken place. Consistent with this proposal are

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Table 1
Mechanical therapeutic interventions for preventing myocardial reperfusion injury in patients undergoing PPCI
Study
IPost

Therapeutic intervention

Result

Staat et al.
30
Four 60-s cycles of low-pressure inflation/deflation
2005 (66)
of angioplasty balloon
Thibault et al.
38
Four 60-s cycles of low-pressure inflation/deflation
2008 (94)
of angioplasty balloon

Lonborg et al.
118
Four 60-s cycles of low-pressure inflation/deflation
2010 (95)
of angioplasty balloon
Sorensson et al. 76
Four 60-s cycles of low-pressure inflation/deflation
2010 (96)
of angioplasty balloon


Tarantini et al.
78
Four 60-s cycles of low-pressure inflation/deflation of
2012 (97)
angioplasty balloon; IPost protocol delivered in stent
Freixa et al.
79
Four 60-s cycles of low-pressure inflation/deflation of
2012 (98)
angioplasty balloon; IPost protocol delivered in stent
Engstrom et al. 2,000
Four 30-s cycles of low-pressure inflation/deflation
2012 (99);

of angioplasty balloon
DANAMI-3

Reduction of MI size by 36% (72-hr AUC CK);

improved myocardial blush grade
Reduction of MI size by 40% (72-hr AUC CK); reduction of
MI size by 39% at 6 mo, as assessed with SPECT;
7% increase in EF, as assessed with ECG, at one year
Reduction of MI size by 19% at 3 mo, as assessed with CMR;
31% increase in myocardial salvage index
No difference in 48-hr AUC CK-MB or Trop-T; no difference
in myocardial salvage, as assessed with CMR, on days
79; significant increase in myocardial salvage
in patients with large AAR (>30% of LV)
Trend toward increased MI size; increased adverse events
Worse myocardial salvage; no difference in MI size
Ongoing phase 3 study investigating the effect
of IPost on death and HHF

RIC
Botker et al.
142
(77, 100)
Rentoukas et al. 92
2010 (101)

Four 5-min cycles of inflation/deflation of

cuff placed on upper arm, in the ambulance
Three 4-min cycles of inflation/deflation of cuff placed
on upper arm, delivered at hospital prior to PPCI

Increase in myocardial salvage index from 0.55 to 0.75; patients

with anterior STEMI with occluded arteries showed most benefit
Less STR and smaller Trop-I peak; additive effect
with i.v. morphine

Cooling to 35C prior to PPCI by i.v. infusion of

12 liters of cold saline and cooling with
Philips InnerCool RTx Endovascular System
Cooling to 35C prior to PPCI by i.v. infusion of
12 liters of cold saline and cooling with
Philips InnerCool RTx Endovascular System

Reduction in MI size as % of AAR, as assessed with CMR at

4 days (30% vs 48%); 43% reduction in peak and
cumulative Trop-T release
Ongoing multicenter study investigating whether cooling prior to
PPCI reduces MI size (as a % of AAR) on CMR at 4 days

IC hyperbaric hyperoxemic reperfusion

started after PPCI and continued for 90 min

No difference in 14-day MI size as assessed with SPECT;

patients with anterior STEMI <6 h showed improvementsA

IC hyperbaric hyperoxemic reperfusion

started after PPCI and continued for 90 min

No difference in 14-day MI size as assessed with SPECTA

Therapeutic hypothermia
Gotberg et al.
20
2010 (102);
RAPID-MI-ICE
Erlinge et al.
120
2012 (103);
CHILL-MI
Therapeutic hyperoxemia
ONeill et al.
269
2007 (78);
AMIHOT I
Stone et al.
281
2009 (104);
AMIHOT II

APooled analysis of the results from AMIHOT I/II suggested beneficial effects on MI size. CMR, cardiac MRI; EF, ejection fraction; HHF, hospitalization for heart
failure; STR, ST-segment resolution. CK, creatine kinase; CK-MB, CK (muscle and brain iso-enzyme); IC, intracoronary; Trop-T, troponin-T; Trop-I, troponin-I.

experimental data demonstrating an increase in MI size as reperfusion time progresses, suggesting a wave front of reperfusion injury
that progress with time (3, 50, 51). However, this is a controversial
area of research, and some experimental studies have failed to demonstrate an increase in MI size with reperfusion time (52).
Several experimental studies have reported that administering
cardioprotective agents such as erythropoietin (anti-apoptotic)
(53), PI3K-/ inhibitors (anti-inflammatory) (54), intracoronary aqueous oxygen (55), and IPost (anti-apoptotic and antiinflammatory) (56) from 30 minutes to 24 hours into myocardial
reperfusion may still limit acute MI size at 72 hours. Whether this
therapeutic window exists in patients with STEMI who are under

going PPCI is of great investigational interest, as such a window

would allow a cardioprotective intervention to be administered
some hours after the PPCI procedure. This area of research is still
in its infancy but may suggest or provide an additional therapeutic
window to target late into the reperfusion phase.
Therapeutic strategies for reducing acute myocardial
ischemic injury
For patients presenting with a STEMI, the most effective and wellestablished therapeutic strategy for reducing acute myocardial
ischemic injury and limiting MI size is timely myocardial reperfusion using either thrombolytic therapy or PPCI. The duration

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Table 2
Pharmacologic therapies for preventing myocardial reperfusion injury in PPCI patients
Study
Adenosine

Ross et al. 2005 (105);

2,118
AMISTAD II

Anti-inflammatory agents

Armstrong et al.
5,745
2007 (72);
APEX-MI
Atar et al.
232
2009 (49);
FIRE

Atrial natriuretic peptide

Kitakaze et al. 2007 (106); 569

J-WIND

Atorvastatin

Therapeutic intervention

Result

Infusion of adenosine 50 or 70 g/kg/min

i.v. for 3 h after PPCI

No difference in death or HHF at 6 months; post hoc analysis

showed benefits in patients presenting within 3.2 h

Pexelizumab 2 mg/kg i.v. bolus given over No difference in deaths at 30 days (pexelizumab, 4.1%; placebo, 3.9%)
10 min prior to PPCI, followed by 0.05 mg/kg/h
infusion for 24 hours
Bolus of FX06 (200 mg i.v.) immediately
No difference in MI size at 5 days or 4 months, as assessed
prior to guidewire crossing obstruction,
with CMR; no difference in MI size, as assessed with Trop
repeated within 10 min
Carperitide infusion at 0.025 g/kg/min i.v.
increase in LVEF at 612 months

Kim et al.
171
Oral atorvastatin 80 mg vs atorvastatin I
2010 (107);
10 mg prior to PPC
STATIN STEMI
Hahn et al.
173
Oral atorvastatin 80 mg versus atorvastatin
2011 (108)
no difference in perfusion
Post et al. 2012 (109);
52
Oral atorvastatin 80 mg versus atorvastatin
REPARATOR
10 mg prior to PPCI

CsA

Piot et al. 2008 (80),

58
CsA (2.5 mg/kg i.v.) 10 min prior to PPCI
Mewton et al. 2010 (110)


Ovize et al. 2012 (111);
972
CsA (2.5 mg/kg i.v.) 10 min prior to PPCI
CIRCUS

Delcasertib

Lincoff et al. 2011 (112);

1,083
PROTECTION-AMI

EPO

Delcasertib at 50, 150, and 450 mg/h i.v. for

24 hours started prior to PPCI

Reduction in MI size by 14.7% (total CK AUC);

2.5% increase in LVEF at 612 months
No effect on death, MI, or revascularization; no difference
in MI size (CK-MB maximum); improved myocardial
perfusion (blush grade, STR)
No effect on MI size, as assessed with SPECT at days 514;
no difference in perfusion
No effect on indexed LVESV; no difference in MI size or perfusion
size or perfusion
Reduction of 44% in MI size (72-h AUC total CK);
20% reduction in MI size (as assessed with CMR in
a subset of 27 patients); 28% reduction in MI size
and smaller LVESV on CMR at 6 months
Ongoing phase 3 clinical trial investigating whether CsA
improves clinical outcomes at one year (total mortality;
HHF; increase in LV end-diastolic volume >15%
No difference in infarct size as assessed with CK-MB AUC;
takes 530 min to reach steady state after beginning infusion

Voors et al.
529
EPO epoetin- 60,000 IU i.v. within
2010 (113);
3 hours after PPCI
HEBE-III
Ott et al.
138 EPO epoetin- 33,000 IU i.v. immediately after PPCI,
2010 (114);
repeated after 24 and 48 hours
REVIVAL-3
Ludman et al.
52
EPO epoetin- 50,000 IU i.v. prior to PPCI,
2011 (115)
repeated after 24 hours

No difference in LVEF at 6 weeks; no difference in MI size

(as assessed using AUC CK-MB or Trop-T); more major
cardiac adverse events occurred with EPO
No difference in LVEF at 6 months, as assessed
with CMR; no difference in MI size (assessed with CMR
after 5 d and 6 mo)
No difference in MI size at 3 days using CMR and Trop-T;
2-fold higher incidence of MVO on CMR

Lonborg et al.
107
Infusion of exenatide (25 mg in 250 ml saline i.v.)
2011 (81, 116)
started 15 min prior to PPCI and infused for 6 h

Increase in myocardial salvage index at 90 days by CMR

(0.71 vs. 0.62); reduced MI size as % of AAR at 90 days as
assessed with CMR (0.30 vs. 0.39); reduced MI size was
observed for patients presenting <132 min (8% vs 11%)

Exenatide

GIK therapy

Mehta et al. 2005 (117);

20,201
Infusion of GIK (25% glucose, 50 U/l insulin,
CREATE-ECLA
80 mEq/l potassium infused i.v. at

1.5 ml/kg/h) for 24 h
Selke et al. 2012 (58);
357
Infusion of GIK solution (i.v. for 12 h), begun
IMMEDIATE
in the ambulance for suspected STEMI patients

No difference in 30-d mortality (9.7% placebo vs 10.0% GIK);

majority of patients were treated by thrombolysis and not PPCI;
GIK was begun after reperfusion in 68% of patients
No difference in progression to MI, but reduction in
composite outcome of cardiac arrest or in-hospital
mortality was 6.1% with GIK vs 14.4% with placebo

Frenneaux et al.
200
Sodium nitrite i.v. prior to PPCI
2012 (118); NIAMI
Mathur et al. 2012 (119);
80
Intracoronary bolus of sodium nitrite given
NITRITE-AMI
5 min prior to PPCI

Ongoing phase 2 trial to investigate whether i.v. sodium nitrite

reduces MI size (expressed as % of the AAR on CMR)
Ongoing phase 2 trial investigating whether intracoronary sodium
nitrite reduces MI size (48-h total AUC CK)

Sodium nitrite

TRO40303

Atar et al. 2012 (120);

180
MitoCare

Peripheral i.v. infusion of TRO40303

prior to PPCI

Ongoing phase 2 trial investigating whether TRO40303

reduces MI size (72-h AUC CK and Trop-I)

CsA, cyclosporin A; EPO, erythropoietin; LVESV, LV end-systolic volume.

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of acute myocardial ischemia is a critical determinant of MI size,
and as such, minimizing the time from chest pain onset to PPCI
is the treatment priority. In the pre-hospital phase this includes
increasing patient awareness of the symptoms of a MI (in order
to minimize the delay before the emergency services are contacted), and the rapid diagnosis and transfer of STEMI patients to
the PPCI center (57). At the hospital, reducing acute myocardial
ischemic injury requires a treatment protocol that minimizes the
door-to-PPCI time. In situations in which the transfer time to the
PPCI center is prolonged, there is an opportunity for paramedics to administer a therapeutic strategy in the ambulance that can
delay acute myocardial ischemic injury until PPCI has taken place.
In this respect, the recently published IMMEDIATE clinical trial
investigated the effects of metabolic modulation using an intravenous glucose insulin potassium (GIK) therapy administered in
the ambulance to patients experiencing acute myocardial ischemia
with suspected acute coronary syndrome. However, the study
failed to find any difference in the primary endpoint of progression to acute MI, although patients with STEMI administered GIK
therapy experienced less cardiac arrest and in-hospital mortality
compared with those administered placebo (58).
Therapeutic strategies for reducing myocardial
reperfusion injury
For patients presenting with a STEMI in whom acute myocardial
ischemia has already taken place, the opportunity to intervene is
limited to after the onset of myocardial ischemia or at the time of
myocardial reperfusion (PPCI). The process of myocardial reperfusion by PPCI continues to be improved with earlier reperfusion,
advances in PCI technology, and the introduction of more efficacious antiplatelet and antithrombotic agents for maintaining
the patency of the infarct-related coronary artery. However, there
remains no effective therapeutic agent for preventing either MVO
or lethal myocardial reperfusion injury in patients with STEMI
who are undergoing PPCI. Unfortunately, therapeutic targeting
of the individual components of lethal myocardial reperfusion
injury, including oxidative stress, calcium overload, pH correction,
and, more recently, inflammation have produced disappointing
results, the reasons for which are discussed below (59, 60).
However, a number of emerging therapeutic strategies for preventing lethal myocardial reperfusion injury have shown promise in small proof-of-concept clinical studies, and multicenter
randomized clinical trials are currently underway to investigate the effects of these strategies on clinical outcomes in PPCI
patients (Tables 1 And 2).
IPost. In contrast to unimpeded reperfusion, IPost is intermittent reperfusion of the acute ischemic myocardium, which has
been reported to prevent myocardial reperfusion injury and reduce
MI size by 40%50% (61). It must be appreciated that IPost represents a form of modified reperfusion that was demonstrated
in the 1980s to be beneficial in the form of gradual reperfusion
(6265). Staat et al. (66) first applied IPost to the clinical setting
of PPCI: immediately after direct stenting, coronary blood reflow
was allowed for 60 seconds, following which the angioplasty balloon was inflated upstream of the stent for 60 seconds to occlude
coronary blood flow, and this cycle was repeated 4 times in total
(Table 1). The results of this study confirmed the existence of lethal
myocardial reperfusion injury in humans (67). A number of clinical
studies have subsequently confirmed the beneficial effects of IPost,
although not all studies have had positive results (Table 1). A large

multicenter randomized clinical trial is now underway in Denmark

(DANAMI-3) to investigate the effects of IPost on clinical outcomes
in PPCI patients (Clinicaltrials.gov identifier NCT01435408).
Remote ischemic conditioning. IPost requires an invasive therapeutic intervention applied directly to the heart. However, the heart
can be protected against acute IRI from a distance, by applying
one or more cycles of brief, nonlethal ischemia and reperfusion
to another organ or tissue, a phenomenon that has been termed
remote ischemic conditioning (RIC) (68, 69). In the clinical setting, RIC has been achieved noninvasively by simply inflating
and deflating a blood pressure cuff placed on the upper arm to
induce three 5-minute cycles of ischemia and reperfusion (70, 71).
This therapeutic approach has been reported to be beneficial
in patients undergoing cardiac surgery (7275) and in patients
undergoing elective PCI (76). Most recently, Botker et al. (77) demonstrated that RIC applied by a paramedic to patients with STEMI
in transit to the PPCI center improved myocardial salvage compared with control patients (Table 1). Again, the patients that benefited most from this therapeutic intervention were those presenting with an anterior STEMI and an occluded coronary artery (77).
Whether RIC can actually improve clinical outcomes following
PPCI is currently unknown.
Therapeutic hyperoxemia and hypothermia. Two other mechanical interventions that have been reported in animal studies to
be beneficial against myocardial reperfusion injury include
therapeutic hyperoxemia (78) and hypothermia (79). Hyperbaric
oxygen reduces MI size by decreasing tissue edema, reducing formation of lipid peroxide radicals, altering nitric oxide synthase
expression, and inhibiting leukocyte adherence and plugging in
the microcirculation. Lowering myocardial temperature during
ischemia to 32C33C can limit MI size in experimental studies by reducing metabolic demand, reducing the inflammatory
response, decreasing platelet aggregation, and increasing myocardial efficiency. Proof-of-concept clinical studies in PPCI patients
have demonstrated these therapeutic interventions to be potentially promising (Table 1).
Pharmacologic agents for preventing myocardial reperfusion injury.
Elucidation of the mechanistic pathways underlying IPost have
resulted in the identification of a number of new targets to prevent
myocardial reperfusion injury. These include pharmacologic modulators of the reperfusion injury salvage kinase prosurvival pathway, such as adenosine, atrial natriuretic peptide, atorvastatin,
erythropoietin, exenatide, delcasertib, and GIK (Table 2). Other
agents are known to preserve mitochondrial function during acute
IRI, such as cyclosporin A, sodium nitrite, and TRO40303 (Table 2).
However, the results of clinical studies investigating these agents
have been mixed, with the most promising pharmacologic agents
being cyclosporin A (80) and exenatide (ref. 81 and Table 2).
Cardiac MRI for assessing acute myocardial IRI
Recent advances in cardiac magnetic resonance (CMR) imaging
have made it possible to retrospectively assess several key features
of acute myocardial IRI in patients with STEMI who have undergone PPCI treatment. Performing a CMR scan in the first week
following PPCI allows the detection and the quantification of several important prognostic imaging biomarkers including MI size,
MVO, and intramyocardial hemorrhage (82). There is also the
potential to measure myocardial salvage, with the AAR delineated
by T2-weighted imaging of myocardial edema (8385). However,
this technique for measuring the AAR has its limitations and fur-

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ther study is required to validate its use (8688). A repeat scan
performed 4 to 6 months later provides an assessment of final MI
size and post-MI LV remodeling in PPCI patients. Therefore, the
availability of CMR allows the assessment of the efficacy of therapeutic strategies for preventing acute myocardial IRI and provides
robust surrogate endpoints of cardioprotection for future clinical
studies. However, it must be appreciated that surrogate endpoints
to assess the efficacy of therapeutic interventions should be used
to inform the design of larger, multicenter, randomized clinical
trials with hard clinical endpoints.
Improving translation of cardioprotection
The research field of cardioprotection has been plagued by the large
number of failed attempts to translate promising therapeutic strategies for preventing lethal myocardial reperfusion injury discovered
in the basic science laboratory into the clinical setting. The reasons
for this failure have been discussed in detail elsewhere (59, 60, 89, 90)
and can be summarized as the use of inappropriate experimental
animal models, the clinical testing of inconclusive therapies, and
poor clinical trial design. Many experimental MI models fail to represent the clinical setting of an MI in terms of comorbidities (such
as age, diabetes, dyslipidemia, and hypertension) and concomitant
medication, the presence of which may interfere with the therapeutic cardioprotective intervention (91). The therapeutic intervention should confer conclusive cardioprotection in all experimental animal models tested before being investigated in the clinical
setting. The National Heart, Lung, and Blood Institute (NHLBI)
formed the CAESAR Consortium, a network of research centers in
the United States (92) in which small and large animal models of
experimental MI are used to investigate any promising cardioprotective strategies using an approach akin to a multicenter, randomized, controlled clinical trial. Finally, in terms of improving clinical
study design, several recent strategy documents (60, 92) have suggested the following guidelines: only patients with anterior STEMI
with complete occlusion of coronary flow and no collaterals should
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be included; the therapeutic intervention should be administered

prior to myocardial reperfusion; and relevant endpoints pertinent
to acute cardioprotection should be used.
Conclusions
Acute myocardial IRI is the major cause of the detrimental effects
of CHD on the myocardium. This form of myocardial injury is
characterized in STEMI patients who present with acute myocardial ischemia, in whom treatment priority is timely and effective myocardial reperfusion using either thrombolytic therapy or
PPCI. Although improvements in myocardial reperfusion continue to take place in terms of new antiplatelet and antithrombotic
agents, there is still no effective therapeutic strategy for preventing
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ongoing research, with the recent discovery of several mechanical
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Acknowledgments
We thank the British Heart Foundation (program grant
RG/03/007) for their ongoing funding and support. D.J. Hausenloy is funded by a British Heart Foundation Senior Clinical
Research Fellowship (FS/06/023). This work was undertaken at
the University College London Hospitals and University College
London, which received a portion of funding from the Department of Healths National Institute for Health Research Biomedical Research Centres funding scheme.
Address correspondence to: Derek M. Yellon, Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, United Kingdom. Phone: 44.203.447.9888; Fax:
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The Journal of Clinical Investigationhttp://www.jci.orgVolume 123Number 1January 2013